Involvement of Cortical Excitatory Projections in Cocaine Addiction

PROJECT SUMMARY / ABSTRACT There is no effective clinical treatment to prevent relapse to psychostimulants, although extensive studies have been done focusing on the medial prefrontal cortex and nucleus accumbens. Breakthroughs in the clinical settings rely heavily on a better understanding of brain adaptations, which may explain both chronic drug seeking and taking behaviors. Persistent drug seeking behaviors after a prolonged withdrawal period, as the most accepted laboratory animal model in predicting the risk of relapse, is not exclusively motivation-driven. Here we propose that by the passage of the withdrawal period, the motor/habit components of drug seeking behaviors increase and gradually take over the initial motivational components. The cortical pyramidal neurons (CPNs) in the Supplementary Motor Cortex (M2) will be the central focus of this proposal. Our hypothesis is that high excitability in M2 CPNs and enhanced glutamate release at the M2 CPN terminals in the striatum lead to high drug seeking behaviors at later withdrawal stages after cocaine exposure. Three specific Aims are proposed to, first, examine the excitability of CPNs in the M2 region (Aim 1) and the excitatory transmission in the M2-DLS projection (Aim 2), and then to prevent cocaine seeking (Aim 3) in Sprague Dawley (SD) rats with a history of intravenous self-administration of cocaine. Mechanisms of relapse will be investigated in the motor CPNs in the M2 area and their target dorsolateral striatal synapses. Our hope is to pave the way not only to provide an original perspective in our understanding of addiction-like behaviors, but also to propose novel targets for clinical management of drug relapse.